Congenital Insensitivity To Pain Research Articles

Recurrent Digital Infections and Osteomyelitis in Monozygotic Twins With Congenital Analgesia and Compulsive Onychophagia

Congenital insensitivity to pain is a rare sensory neuropathy that manifests with multiple and recurrent injuries secondary to a lack of negative pain stimuli. When present with compulsive onychophagia, prompt recognition and behavioral management to prevent chronic digital infection or amputation is imperative. We present the case of two 7 year-old monozygotic twins that presented with congenital insensitivity to pain and compulsive onychophagia without directed parental counseling or behavioral modification strategies. The presenting child was noted to have an acute digital felon and osteomyelitis of several distal phalanges, and the sister had a similar history with distal phalangeal amputations. The occurrence of these overlapping disorders in monozygotic twins has not been previously reported, however, patient and parental education with behavioral modifications of injurious and compulsive behavior is the cornerstone of management. In addition, we have provided a review of the diagnosis for clinical differentiation.

Global Nav1.7 KO mice recapitulate phenotype of congenital indifference to pain reported in humans

Human genetic studies have shown that the Nav1.7 sodium channel is critical for pain perception. Gain-of-function mutations lead to an inherited erythromelalgia , and loss-of-function mutations result in congenital indifference to pain (CIP). The corresponding global Nav1.7 mouse knockout has been described as neonatal lethal. Accordingly, it is somewhat uncertain to what extend Nav1.7 governs pain in mammals, especially since some differences in Nav1.7 expression between primates and rodents have been reported.

Two-dimensional video gait analyses in patients with congenital insensitivity to pain

Purpose: To clarify the features of gait in patients with congenital insensitivity to pain (CIP) by analyzing the video-recorded gait.Methods: Eleven patients with the diagnosis of hereditary sensory and autonomic neuropathy (HSAN) type 4 or 5 and 15 healthy participants were enrolled in this study. Gait was analyzed using two-dimensional (2D) digital video and video analysis software. Walking speed, cadence, step length, stance phase duration, and heel contact to foot flat period were compared between patients and healthy participants.Results: The results showed that walking speed and heel contact angular velocity were significantly higher (p < 0.05), and step length was significantly longer (p < 0.05) in CIP patients, especially in the younger age group.Conclusion: Young patients with CIP walked faster, with a longer step length and higher heel contact angular velocity than young control participants. These results may explain the frequency of lower extremity injuries in CIP patients.

Infrequent SCN9A mutations in congenital insensitivity to pain and erythromelalgia

ObjectiveMutations in SCN9A have been reported in (1) congenital insensitivity to pain (CIP); (2) primary erythromelalgia; (3) paroxysmal extreme pain disorder; (4) febrile seizures and recently (5) small fibre sensory...

Identification of Novel NaV1.7 Antagonists Using High Throughput Screening Platforms

Congenital Insensitivity to Pain (CIP) is a loss of function mutation resulting in a truncated NaV1.7 protein, suggesting a pivotal role in pain signaling and rendering it an important pharmaceutical target for multiple pain conditions. The structural homology in the NaV-channel family makes it challenging to design effective analgesic compounds without inducing for example cardiotoxicity or seizure liabilities. An additional approach to structural isoform selectivity is to identify compounds with use- or state-dependent profiles, i.e. inhibition efficacy based on the gating of the ion channel. In general nerve cells in damaged or inflamed tissue are more depolarized and electrically active compared to healthy nerve cells in for instance the heart. This observation has led to the design of two types of screening protocols emulating the voltage condition of peripheral neurons or cardiac tissue. The two voltage protocols have been developed to identify both use- and state-dependent antagonists. In this paper we describe an attempt to merge the two different protocols into one to increase screening efficacy, while retaining relevant state- and use-dependent pharmacology. The new protocol is constructed of two stimulation pulses and a slow voltage ramp for simultaneous assessment of resting and state-dependent block. By comparing all protocols we show that the new protocol indeed filter compounds for state-dependence and increase the prediction power of selecting use-dependent compounds.

Abnormal capacity for grip force control in patients with congenital insensitivity to pain

Congenital insensitivity to pain (CIP), which is an extremely rare sensory neuropathy, is defined as the absence of normal responses to noxious stimuli. Although motor function is not directly impaired in CIP patients, it is likely that the sensory deficit affects the motor control system. In order to characterize motor capacity in CIP patients, we here measured grip force and acceleration of a held object in 12 patients with CIP and 12 age-matched able-bodied subjects. The results demonstrated that the grip force during the object grasp-lift-holding task was significantly greater, less reproducibility and greater fluctuation in the acceleration of the object in CIP patients than in normal subjects. Moreover, some patients showed absence of temporal coupling between the grip and load force, suggesting that anticipatory modulation of the grip force was at least partly impaired. As far as the authors know, this is the first study to characterize motor control ability in patients with CIP. The observed abnormal motor capacity can be at least partly attributed to a lack of sensory inputs mediated by Aδ and unmyelinated C-, specifically C-tactile, fibers. The present results may provide information useful for the prevention of secondary injury and education for patients during the developmental stage.

Chronic plantar ulcer secondary to congenital indifference to pain

Congenital indifference to pain (CIP) is a rare condition characterised by painless injuries beginning in early life, with normal sensory exam findings. Young people with inexplicable, painless chronic wounds may present to the plastic surgeon for surgical management. Given the young age of onset and high likelihood of postoperative failure, alternative options for closure of non-healing wounds should be considered. We present the case of a 17-year-old boy with congenital indifference to pain and successful management of his longstanding plantar ulcer.

Two NovelSCN9AGene Heterozygous Mutations May Cause Partial Deletion of Pain Perception

The physiological sensation of pain and rapid response to stimuli serve as an adaptive way to avoid harmful situations. Our purpose was to investigate why this protection disappears or almost disappears for patients with congenital indifference to pain (CIP). The study was designed as a case report by scanning the candidate genes within CIP patients. The study was set at the Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. We reported patients from two Chinese families that showed insensitivity to pain and were diagnosed with CIP by a neurologist. Different from recently reported studies, our patients were not entirely painless, but demonstrated little pain sensation from injuries. The measures made were novel mutations within SCN9A. Sequence analysis of candidate genes of two affected individuals identified two novel heterozygous mutations (M899I and M932L) in the SCN9A gene. Furthermore, a novel nonsynonymous single-nucleotide polymorphism (SNP) within the SCN9A gene was revealed in affected proband and several unaffected family members. This polymorphism (c. 3312G&T, which produces the amino acid substitution V1104L in human Nav1.7), is present in 6.5% of healthy Chinese. We speculate that the mutations may be the cause of partial deletion of pain perceptionin in our probands, and the novel polymorphism V1104L may have a predictive role in the pain sensation of healthy individuals.

New molecules for the treatment of pain

To inform on preclinical and early clinical advances in the effort to identify novel classes of analgesic drugs. Human genetic and animal preclinical studies have identified several mechanisms that appear to make important contributions to abnormal pain states. From human genetics, a small number of patients with mutations in the genes encoding nerve growth factor/TrkA signaling and in a particular sodium channel subunit (SCN9a, encoding Nav1.7) show congenital analgesia with limited other effects. There are, therefore, considerable hopes that pharmacological manipulation of these systems in chronic pain patients might be an effective analgesic strategy. A substantial body of preclinical work has focussed on interactions between the immune and the nervous system and this has led to the identification of a number of novel putative inflammatory mediators and receptors, which are being explored as potential analgesic targets. A recent preclinical effort has studied intracellular signaling cascades recruited in the transition from acute to chronic pain states - the analgesic opportunities on offer here are being pursued in early clinical trials. Existing analgesic drugs are small in number, limited in efficacy and associated with significant side-effects. There is, therefore, a need for new pain medications. In the last decade or so, clinical and preclinical research have progressed rapidly and this work has identified multiple plausible drug targets, which are currently being evaluated. We review here the rationale of some of the most promising mechanisms and report on progress in drug development.

Congenital insensitivity to pain with anhidrosis and old fracture: a case report

先天性无痛无汗症又称遗传性感觉和自主神经障碍Ⅳ型,是一种罕见的先天性常染色体隐性遗传病.报道1例如下. 患儿男,3岁2个月,因右膝关节肿胀20 d于2009年5月4日入院.体检:右膝关节处肿胀,于膝关节前内侧可触及软组织包块,无移动,界限不清;右足肿胀.患儿无疼痛,用针刺全身各部位均无痛感.碘发汗定性试验和热发汗定性试验均证明无汗.既往史:其母陈述患有无汗症3年,全身各部位不出汗,反复发热。

Congenital insensitivity to pain: novel SCN9A missense and in-frame deletion mutations.

SCN9A encodes the voltage-gated sodium channel Nav1.7, a protein highly expressed in pain-sensing neurons. Mutations in SCN9A cause three human pain disorders: bi-allelic loss of function mutations result in Channelopathy-associated Insensitivity to Pain (CIP), whereas activating mutations cause severe episodic pain in Paroxysmal Extreme Pain Disorder (PEPD) and Primary Erythermalgia (PE). To date, all mutations in SCN9A that cause a complete inability to experience pain are protein truncating and presumably lead to no protein being produced. Here, we describe the identification and functional characterization of two novel non-truncating mutations in families with CIP: a homozygously-inherited missense mutation found in a consanguineous Israeli Bedouin family (Nav1.7-R896Q) and a five amino acid in-frame deletion found in a sporadic compound heterozygote (Nav1.7-ΔR1370-L1374). Both of these mutations map to the pore region of the Nav1.7 sodium channel. Using transient transfection of PC12 cells we found a significant reduction in membrane localization of the mutant protein compared to the wild type. Furthermore, voltage clamp experiments of mutant-transfected HEK293 cells show a complete loss of function of the sodium channel, consistent with the absence of pain phenotype. In summary, this study has identified critical amino acids needed for the normal subcellular localization and function of Nav1.7. © 2010 Wiley-Liss, Inc.

A Nonsense Mutation in the SCN9A Gene in Congenital Insensitivity to Pain

Background: Congenital insensitivity to pain (CIP) (OMIM 243000) is a rare autosomal-recessive disorder. Clinically, CIP is characterized by insensitivity to all modalities of pain except neuropathic pain, and recurrent injuries frequently go unnoticed. CIP is caused by mutations in the SCN9A gene encoding for the Na1.7 channel. Methods: We analyzed the DNA from members of a consanguineous Pakistani family for mutations in the SCN9A gene through direct sequencing after performing linkage studies. Results: We identified a novel missense mutation designated R523X in all affected individuals. A screening assay ruled out the possibility of polymorphism. Conclusion: We identified a novel mutation in the Na1.7 channel leading to CIP, extending the spectrum of mutations in the Na1.7 channel, and enhancing our understanding of the physiology of pain.

Anesthetic Management of a Patient with Congenital Insensitivity to Pain with Anhidrosis Measuring the Plasma Catecholamine Levels

先天性無痛無汗症患者に対し，左第1趾切断術の麻酔をBISモニター使用下にプロポフォールの持続静脈内投与による全身麻酔で行い，十分な鎮静と安定した循環動態管理ができた．その際に交感神経の興奮を調査するため，麻酔導入直後と術中に血中カテコラミン値を測定した．その結果アドレナリン，ノルアドレナリン，ドパミンの血中濃度は導入直後，術中ともに低値を示し，変化は認めなかった．本症例においては，手術中の刺激に対し交感神経の興奮が認められないことが確認できた．

Sensory phenotype assessment in a young girl affected by congenital insensitivity to pain (CIPA)

Pediatric AnesthesiaVolume 17, Issue 12 p. 1237-1237 Free Access Sensory phenotype assessment in a young girl affected by congenital insensitivity to pain (CIPA) This article corrects the following: Sensory phenotype assessment in a young girl affected by congenital insensitivity to pain (CIPA) VALERIA BACHIOCCO MD, BERGAMASCHI ROSALBA MD, MONDARDINI MARIA CRISTINA MD, BRONZETTI GABRIELE MD, Volume 17Issue 11Pediatric Anesthesia pages: 1105-1110 First Published online: September 7, 2007 First published: 01 November 2007 https://doi.org/10.1111/j.1460-9592.2007.01752_1.xAboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Valeria Bachiocco, Bergamaschi Rosalba, Mondardini Maria Cristina and Bronzetti Gabriele The author of this paper wishes it to be known that the authors’ names should read as follow: Valeria Bachiocco, Rosalba Bergamaschi, Maria Cristina Mondardini and Gabriele Bronzetti Reference 1 Bachiocco V, Rosalba B, Cristina MM, Gabriele B. Sensory phenotype assessment in a young girl affected by congenital insensitivity to pain (CIPA). Ped Anesth doi: DOI: 10.1111/j.1460-9592.2007.02338.xWiley Online LibraryWeb of Science®Google Scholar Volume17, Issue12December 2007Pages 1237-1237 ReferencesRelatedInformation

Sensory phenotype assessment in a young girl affected by congenital insensitivity to pain (CIPA)

Sensory phenotype was assessed in a young girl affected by congenital insensitivity to pain (CIPA) scheduled for an open surgical drainage. The sensory profile showed that only the Abeta fibers were functioning normally, whereas Adelta and C fibers did not respond to nociceptive stimuli. On the basis of these findings and the results of cardiovascular reflexes, she was submitted to abscess incision and debridement under midazolam sedation alone. She did not report pain or other discomfort during surgery. The sensory (and sympathetic) assessment may have a high potential value in planning anesthesia and analgesia in children with CIPA. This psychophysical procedure could be introduced as standard component of clinical evaluation before surgery.

Loss‐of‐function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations

Congenital indifference to pain (CIP) is a rare condition in which patients have severely impaired pain perception, but are otherwise essentially normal. We identified and collected DNA from individuals from nine families of seven different nationalities in which the affected individuals meet the diagnostic criteria for CIP. Using homozygosity mapping and haplotype sharing methods, we narrowed the CIP locus to chromosome 2q24-q31, a region known to contain a cluster of voltage-gated sodium channel genes. From these prioritized candidate sodium channels, we identified 10 mutations in the SCN9A gene encoding the sodium channel protein Nav1.7. The mutations completely co-segregated with the disease phenotype, and nine of these SCN9A mutations resulted in truncation and loss-of-function of the Nav1.7 channel. These genetic data further support the evidence that Nav1.7 plays an essential role in mediating pain in humans, and that SCN9A mutations identified in multiple different populations underlie CIP.

Congenital insensitivity to pain with anhidrosis and progressing acro-osteolysis: a case report with 7-year follow-up

在到疼痛的敏感先天是稀罕混乱，在 1932 的首先描述的 byDearborn。自从发现在比 60 个案例在 1983,2 少数与汗缺乏或世袭感觉神经病类型 IV 伤害是的敏感先天到有汗缺乏和进行的 acro-osteolysis 的疼痛的 reported.3 Congenitalinsensitivity 是痛苦的感觉的缺席在出生以后描绘的很稀罕的混乱。如果疼痛感觉是不在的，严重问题可以产生，引起对象由自我毁损的牙齿，嘴唇和舌头的口头的结构的损害。病人近来在风险是表示，全身的病与疼痛联系了，例如骨折和联合脱臼。重要地，例如，病人可以与生长承受 fromacro-osteolysis 远侧的极限的 osteolysis。我们在 7 年的后续以后与汗缺乏和 progressingacro-osteolysis 与疼痛的先天的缺席报导一个男孩的临床的特征，并且称早干预的必要性为保守治疗的一种选择。

Is pain the price of empathy? The perception of others' pain in patients with congenital insensitivity to pain

Empathy is a complex form of psychological inference that enables us to understand the personal experience of another person through cognitive/evaluative and affective processes. Recent findings suggest that empathy for pain may involve a 'mirror-matching' simulation of the affective and sensory features of others' pain. Despite such evidence for a shared representation of self and other pain at the neural level, the possible influence of the observer's own sensitivity to pain upon his perception of others' pain has not been investigated yet. The aim of this study was to explore how patients with congenital insensitivity to pain (CIP), who are largely deprived of common stimulus-induced pain experiences, perceive the pain of others. Ratings of verbally presented imaginary painful situations showed that CIP patients' semantic knowledge regarding the pain of others did not differ from control subjects. Moreover, the propensity to infer pain from facial expressions was very similar between CIP patients and control subjects. On the other hand, when asked to rate pain-inducing events seen in video clips in the absence of visible or audible pain-related behaviour, CIP patients showed more variable and significantly lower pain ratings, as well as a reduction in aversive emotional responses, compared with control subjects. Interestingly, pain judgements, inferred either from facial pain expressions or from pain-inducing events, were strongly related to inter-individual differences in emotional empathy among CIP patients, while such correlation between pain judgement and empathy was not found in control subjects. The results suggest that a normal personal experience of pain is not necessarily required for perceiving and feeling empathy for others' pain. In the absence of functional somatic resonance mechanisms shaped by previous pain experiences, others' pain might be greatly underestimated, however, especially when emotional cues are lacking, unless the observer is endowed with sufficient empathic abilities to fully acknowledge the suffering experience of others in spite of his own insensitivity.

The insensate burn: Pain insensitivity syndrome

The depth of burn is related to the temperature of the causative agent and the duration of contact [1]. Duration will be prolonged if the patient is insensate to pain or temperature or is unable to perceive it. Pain insensitivity syndromes can be congenital, such as hereditary sensory and autonomic neuropathy or acquired such as diabetes mellitus associated polyneuropathy. A burn surgeon must remember the existence of such syndromes as this will allow him or her to correctly interpret clinical findings in affected individuals, have a low threshold for seeing such patients early and even suspect the diagnosis of pain insensitivity in patients with recurrent painless burns. We present the first case report in the literature of a child with congenital pain insensitivity syndrome presenting with a burn sustained from an electric hand blow-dryer.

Tension-type headache as the unique pain experience of a patient with congenital insensitivity to pain

Congenital insensitivity to pain (CIP) is a rare clinical syndrome characterized by dramatic impairment of pain perception since birth and is generally caused by a hereditary sensory and autonomic neuropathy (HSAN) with loss of the small-calibre, nociceptive nerve fibres. We report the case of a 32-year-old woman with CIP and a presumptive diagnosis of HSAN type V, who experienced physical pain for the first and unique time in her life shortly after the sudden loss of her brother. This patient had sustained innumerable painless injuries during childhood, including bone fractures and severe burns. The only pain she ever felt consisted in an intense headache, which took place in a context of strong emotional overload and anxiety, 3 weeks after her younger brother died suddenly in a car accident. The description of this inaugural episode of headache fulfilled the diagnostic criteria of episodic tension-type headache. This case strongly suggests that the transcription of the grief of bereavement into physical pain may sometimes occur independently of the peripheral mechanisms of nociception and despite the lack of previous pain experience. In the light of recent experimental data showing that the same neural mechanisms that regulate physical pain may also control the expression of separation distress and the feeling of social exclusion, this unique case helps to better understand why some patients may feel physically hurt after the loss of someone they love.